B细胞活化因子系统在IgA肾病发病中的作用机制研究

IgA nephropathy is a common cause of primary glomerulonephritis and renal failure throughout the world. Glomerular deposits of IgA are characteristics of IgA nephropathy. But the etiology and pathogenesis of this disease still remains unclear. B cell activating factor belonging to tumor necrosis factor family (BAFF) was found to have the function of activating B cell and participating in the class-switching of B cells. In BAFF-Tg mice, the over-expression of BAFF in mice results in mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. However in patients with IgA nephropathy, it is still unclear whether BAFF is increased and associated with the severity of IgA nephropathy. .Our previous research showed that the levels of serum BAFF were elevated in patients with IgA nephropathy and were associated with clinical and pathological features of the disease. Elevated BAFF may play a role in the pathogenesis of IgA nephropathy. In the present study, the further mechanism will be investigated. The study will investigate the relationship between BAFF and the TLRs, monocytes, B cells and the production of abnormal IgA1. The results of the present study will provide more evidence in the pathogenesis, biomarker, and new treating target of IgA nephropathy.

IgA肾病(IgAN)是引起原发性肾小球肾炎和终末期肾衰竭最重要的原因，患者体内异常IgA1的产生可能在发病中具有重要的意义，但具体机制尚不明了。B细胞活化因子（BAFF）是促进B细胞存活以及发生抗体类别转换的重要分子。BAFF转基因小鼠血清中IgA水平增高、系膜区IgA大量沉积，可导致IgAN。那么，IgAN患者是否确实存在BAFF系统异常、进而参与发病过程呢？目前国内、国际缺乏相关研究。.本研究预实验结果首次发现，IgAN患者血清中BAFF水平明显高于健康对照，并与病理类型、肾损伤程度均密切相关，提示BAFF在IgAN发病中可能起到重要作用。因此，本研究将进一步深入研究其机制，明确BAFF系统与TLRs、单核细胞、B细胞及其亚群等与IgAN的关系，以阐明BAFF系统在IgAN发病机制中发挥的作用。本研究将为研究IgAN发病机制、发现潜在的生物标志物和新的治疗靶点提供新的思路。

IgA肾病(IgAN)是引起原发性肾小球肾炎和终末期肾衰竭最重要的原因，患者体内异常IgA1的产生可能在发病中具有重要的意义，但具体机制尚不明了。B细胞活化因子（BAFF）是促进B细胞存活以及发生抗体类别转换的重要分子。BAFF转基因小鼠血清中IgA水平增高、系膜区IgA大量沉积，可导致IgA肾病。那么，IgA肾病患者是否确实存在BAFF系统异常、进而如何参与发病过程，目前国内、国际缺乏相关研究。本研究主要研究内容为研究IgA肾病患者是否有BAFF系统的异常，及其在IgA肾病发病中的机制。本研究主要研究成果包括：完成153例IgA肾病患者、55例正常对照血清、20例疾病对照血清中BAFF、APRIL水平检测，分析了BAFF、APRIL水平与IgA肾病临床、病理的关系，结果发现IgA肾病患者存在BAFF水平异常，并且与其病理分型密切相关；研究了IgA肾病患者BAFF、APRIL受体配体系统发生异常的机制，发现IgA肾病患者B细胞BAFF相关受体表达与正常对照具有升高的趋势，说明BAFF可能与受体共同作用是在IgA肾病发病中具有重要意义；因IgA肾病患者血清中IgA往往发生糖基化异常，采用糖基化异常的IgA对细胞进行刺激，结果发现炎症因子及自噬相关的分子表达变化，但是未发现各组间的明显区别；另外BAFF、APRIL水平在抗肾小球基底膜肾病、原发性小血管炎患者体内的水平也明显增高，并且与临床、病理有关。其中本研究发现的IgA肾病患者血清BAFF水平与临床病理严重性具有相关性，可以作为是IgA肾病程度的非侵入性生物标志物（Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. J Nephrol 2013, 26(4):683-690. ），此为国内、国际上首次提出此观点，为进一步研究IgA肾病的发病机制奠定了一定的基础。